Effects of bilobalide, ginkgolide B and picrotoxinin on GABA A receptor modulation by structurally diverse positive modulators

Ng, Chiu Chin; Duke, Rujee K.; Hinton, Tina; Johnston, Graham A.R.

doi:10.1016/j.ejphar.2017.04.019

Cited by 19 publications

(13 citation statements)

References 47 publications

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“…In turn, GABA was found to partially antagonise bilobalide's inhibitory actions (Kiewert et al, ). One recent study reported that both bilobalide and ginkgolide B selectively inhibited structurally‐varied GABA‐A positive modulator agent actions when tested in Xenopus oocytes (Ng, Duke, Hinton, & Johnston, ).…”

Section: Resultsmentioning

confidence: 99%

“…One recent study reported that both bilobalide and ginkgolide B selectively inhibited structurally-varied GABA-A positive modulator agent actions when tested in Xenopus oocytes (Ng, Duke, Hinton, & Johnston, 2017).…”

Section: Ginkgo Biloba (Maiden Hair)mentioning

confidence: 99%

“…Additionally, another study (Ahmadi, Khalili, Abbasian, & Ghaeli, 2017), in a double-blind RCT with 51 HIV-positive patients, found that 530 mg of V. officinalis extract daily for 4 weeks significantly reduced the anxiety that commonly occurs as a neuropsychiatric side effect of antiretroviral therapy. GABA-A and GABA-C receptors anatagonist; increased GABA levels and glutamic acid decarboxylase enzyme activity Huang et al (2003Huang et al ( , 2004Huang et al ( , 2006Huang et al ( , 2012; Ivic et al, 2003;Kiewert et al, 2007;Ng et al, 2017;Sasaki et al, 1999Sasaki et al, , 2000 EPM, open field, water maze Kuribara et al (2003); Ma et al (2012) Generalised anxiety disorder Woelk et al (2007) Matricaria recutita/Matricaria chamomilla…”

Section: Valeriana Officinalis (Valerian)mentioning

confidence: 99%

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GABA‐modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence

Savage

Firth

Stough

et al. 2017

Phytotherapy Research

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Anxiety disorders are chronic and functionally disabling conditions with high psychological stress, characterised by cognitive symptoms of excessive worry and focus difficulties and physiological symptoms such as muscle tension and insomnia. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter within the central nervous system and is a key target of pharmacotherapies in the treatment of anxiety. Although current pharmaceutical treatments are often efficacious, they may cause undesirable side effects including cognitive decrements and withdrawal symptoms. Plant-based "phytomedicines" may provide novel treatment options, to act as an adjunctive or alternative to existing anxiolytic medications. As such, we conducted a systematic review to assess the current body of literature on anxiolytic phytomedicines and/or phytoconstituents.An open-ended search to 5 July 2017 was conducted using MEDLINE (PubMed), Scopus, and Cochrane library online databases and performed in a stepped format from preclinical to clinical investigations. Eligible studies must have had (a) in vitro evidence of GABA-modulating activity, (b) animal studies using anxiety models to test an anxiolytic effect, and (c) human clinical trials.Ten phytomedicines were identified as having preclinical investigations showing interaction with the GABA system, in addition to human clinical trials: kava, valerian, pennywort, hops, chamomile, Ginkgo biloba, passionflower, ashwagandha, skullcap, and lemon balm. Collectively, the literature reveals preclinical and clinical evidence for various phytomedicines modulating GABA-pathways, with comparative anxiolytic effect to the current array of pharmaceuticals, along with good safety and tolerability profiles.

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Section: Resultsmentioning

confidence: 99%

Section: Ginkgo Biloba (Maiden Hair)mentioning

confidence: 99%

Section: Valeriana Officinalis (Valerian)mentioning

confidence: 99%

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GABA‐modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence

Savage

Firth

Stough

et al. 2017

Phytotherapy Research

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“…This may be due to its potent action on GABA C receptors [57]. Bilobalide also has difering efects to those of picrotoxin on the modulation of GABA A receptors by structurally diferent modulators [60], suggesting a diferent binding proile to picrotoxin to negatively modulate the GABA A receptors.…”

Section: Bilobalide a Nonconvulsant Channel Blockermentioning

confidence: 99%

Antagonists of Ionotropic Receptors for the Inhibitory Neurotransmitter GABA: Therapeutic Indications

Hinton¹,

Johnston²

2018

GABA and Glutamate - New Developments in Neurotransmission Research

Self Cite

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Agents that antagonize the action of GABA on ionotropic receptors are widely used to probe the function of this neurotransmiter. Three such agents are in common use: bicuculline, gabazine, and picrotoxinin. These three agents produce convulsions on systemic administration but act in signiicantly diferent ways. Bicuculline is a competitive antagonist of GABA A receptors. Gabazine is also a competitive antagonist of GABA A receptors, interacting with diferent residues on the receptors. Picrotoxinin is a noncompetitive antagonist acting on the chloride channel of GABA A and several other ionotropic CYSloop receptors including glycine, GABA C , and 5-HT 3 receptors. Many other structurally diverse agents are now known to act as GABA receptor antagonists, providing opportunities for the discovery of agents with selectivity for the myriad of ionotropic GABA receptors. TPMPA is a selective antagonist for GABA C receptors, which are insensitive to bicuculline. Like TPMPA, many antagonists of ionotropic GABA receptors are not convulsants, indicating that there is still much to be learnt about GABA function in the brain from the study of such agents and their possible therapeutic uses. The most recently discovered GABA A receptor nonconvulsive antagonist is S44819, which is subtype selective for α5-containing receptors, and is arousing much interest in relation to cognition.

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“…15 Our group has identified 'neurotrophic' sesquiterpenes jiadifenolide 16 and O-debenzyltashironin 17 as sharing the hyperexcitatory effects of convulsant GABAAR antagonists anisatin 17 and PXN, yet jiadifenolide displays no convulsive signature in mice ( Figure 1a). 15,18 A short synthetic route might allow interrogation of analogs of PXN that similarly reduce its toxicity yet still antagonize GABAA receptors.…”

mentioning

confidence: 99%

Total Synthesis of (–)-Picrotoxinin

Crossley¹,

Tong²,

Lambrecht³

et al. 2019

Preprint

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We report a concise, stereocontrolled synthesis of the neurotoxic sesquiterpenoid, (–)-picrotoxinin (1, PXN). The brevity of the route owes to regio- and stereoselective formation of the [4.3.0] bicyclic core by incorporation of a symmetrizing geminal dimethyl group at C5. A series of strong C–C and C–H bond oxidations convert the C5 gem-dimethyl group to the C15 lactone of PXN. This counterintuitive strategy features the first example of demethylation (C–C bond cleavage) in total synthesis.

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Effects of bilobalide, ginkgolide B and picrotoxinin on GABA A receptor modulation by structurally diverse positive modulators

Cited by 19 publications

References 47 publications

GABA‐modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence

GABA‐modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence

Antagonists of Ionotropic Receptors for the Inhibitory Neurotransmitter GABA: Therapeutic Indications

Total Synthesis of (–)-Picrotoxinin

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